This research proposal is a re-submission of a research project that was submitted as a competitive renewal. The long-term objective of this research proposal is to evaluate and understand potential pharmacotherapies for acute cerebral ischemia so that appropriate drugs might be tested which will reduce or prevent calcium entry into neurons or its consequences. Therapies that will be directed at this will include selected calcium channel blockers, competitive and non-competitive glutamate antagonists, phospholipase antagonists, and possibly newer agents which may act on glycine or sigma sites. Outcome measures will include mortality, light microscopic measurement of ischemic damage, and learning ability. Mechanisms of action of each pharmacotherapy will be determined by cerebral blood flow, immunocytochemical localization and quantitation of calcium calmodulin binding and assessment of CaM-kinase II activity. The second major goal of this research is to expand previous studies of calcium calmodulin binding after global ischemia to better understand calcium activated events in determining irreversible neuronal injury. Studies will be designed to correlate calcium calmodulin binding studies with CaM Kinase II activity and explore the behavior of this kinase after various ischemic intervals.